This UG3/UH3 proposal aims to identify and functionally validate novel genes for frontotemporal lobar degeneration with underlying TDP-43 pathology (FTLD-TDP) through the establishment of an international Sequencing Consortium and an interdisciplinary team of investigators. FTLD comprises a genetically, clinically and pathologically heterogeneous collection of neurodegenerative diseases affecting the frontal and temporal brain regions. Its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. FTLD represents 10-20% of all dementias and is clinically important because of its earlier age at onset compared to Alzheimer's disease (AD) and its dramatic impact on core human qualities, including personality, insight and verbal communication. FTLD-TDP represents the most common FTLD pathological subtype and two major genes have previously been implicated in its genetic etiology, both identified by our study team: mutations in progranulin (GRN) and repeat expansions in the chromosome 9 open reading frame 72 (C9ORF72). However, despite these major advances the cause of the disease in more than 50% of FTLD-TDP patient remains unexplained and much of the pathophysiology underlying FTLD-TDP unknown. In the UG3 phase of this proposal, we will collect biospecimens and detailed phenotypic data from patients with pathologically confirmed FTLD-TDP and patients with clinical diagnoses of semantic variant primary progressive aphasia (svPPA) and frontotemporal dementia with amyotrophic lateral sclerosis (FTD/ALS), highly likely to have TDP-43 pathology from more than 30 sites world- wide (Aim 2). Whole genome sequencing (WGS) will be performed on 625 new FTLD patients and combined with publically available WGS data on 3000 controls to comprise a genetic replication cohort. In Aims 1a+b, WGS data from the replication cohort and a previously generated discovery cohort (500 FTLD-TDP patients and 1000 controls) will be processed through an analytical pipeline developed in collaboration with other FTD consortia. Statistical analyses will subsequently nominate candidate FTLD genes and variants. In the UH3 phase of this proposal, we will prioritize and validate candidate FTLD genes using integrative genomic, transcriptomic, proteomic and statistical analyses in vivo using tissues or cells isolated from FTLD-TDP patients and controls (Aim 3) and ex vivo using human induced pluripotent stem cell models using integrative transcriptomic, proteomic, and high- content imaging assays (Aim 4). Through the discovery of novel FTLD-TDP disease genes we will provide important novel insight into FTLD-TDP pathobiology, advance the development of biomarkers and provide novel targets for therapies.